title: C/EBPα inhibits hepatocellular carcinoma by reducing Notch3/Hes1/p27 cascades.
abstract: OBJECTIVE
  CCAAT/enhancer binding protein α is one of the key transcription factors of the hepatocyte nuclear factors family, which plays a critical role in liver cell proliferation and differentiation. However, the role of CCAAT/enhancer binding protein α in hepatocarcinogenesis remains to be defined.
  
  
  METHODS
  A recombinant adenovirus carrying the C/EBPα gene was constructed to determine its effect on hepatocarcinogenesis in vitro and in vivo.
  
  
  RESULTS
  We demonstrated that overexpression of CCAAT/enhancer binding protein α inhibited the tumourigenicity of Huh7 cells, re-established the expression of certain liver-specific genes and induced G0/G1 arrest. Overexpression of CCAAT/enhancer binding protein α significantly suppressed the proliferation of primary hepatocarcinogenesis cells and tumour associated fibroblasts in vitro. Additionally, intratumoural injection of adenovirus carrying the C/EBPα reduced the growth of subcutaneous hepatocarcinogenesis xenografts in nude mice. Systemic administration of adenovirus carrying the C/EBPα resulted in the eradication of orthotopic liver hepatocarcinogenesis nodules in nude mice. Further, up-regulation of CCAAT/enhancer binding protein α reduced the expression of Notch3, thereby suppressing Hes1 transactivation activity and leading to decreased p27 expression. Overexpression of Hes1 partially abolished the anti-proliferation effect of CCAAT/enhancer binding protein α on Huh7 cells.
  
  
  CONCLUSIONS
  These results suggested that the effect of CCAAT/enhancer binding protein α on hepatocarcinogenesis is partially through by reducing Notch3/Hes1/p27 cascades and CCAAT/enhancer binding protein α may possess a novel therapeutic potential for human hepatocarcinogenesis.
authors.affiliation: Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yi-Chao
authors.initials: YC
authors.lastname: Shi
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Chuan
authors.initials: C
authors.lastname: Yin
authors.forename: Xin
authors.initials: X
authors.lastname: Zeng
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Wen-Ping
authors.initials: WP
authors.lastname: Xu
authors.forename: Ji
authors.initials: J
authors.lastname: Wei
authors.forename: Fei
authors.initials: F
authors.lastname: Chen
authors.forename: Wei-Fen
authors.initials: WF
authors.lastname: Xie
mesh_terms: D000256:Adenoviridae; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D000072056:Transcription Factor HES-1; D014162:Transfection
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D022763:CCAAT-Enhancer-Binding Protein-alpha; D018398:Homeodomain Proteins; D018809:Proliferating Cell Nuclear Antigen; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C499374:NOTCH3 protein, human; C413374:p27 antigen; C078493:HES1 protein, human
keywords: C/EBPα; Hepatocellular carcinoma; Hes1; Notch3